Triple quadrupole mass spectrometry is a well-established and widely used technique for analysis of a variety of substances, including small molecules such as pharmaceuticals and their metabolites, and large molecules such as peptides. Roughly described, a triple quadrupole mass spectrometer consists of two quadrupole mass filters separated by a collision cell. Each of the quadrupole mass filters is constructed from a set of rod electrodes to which oscillatory (e.g., radio-frequency (RF)) and direct current (DC) voltages are applied. The relative magnitudes of the applied RF and DC voltages are varied to adjust the range of mass-to-charge values (m/z's) for which ions are transmitted through the quadrupole mass filter. The collision cell may take the form of another set of rod electrodes, located within a gas-filled enclosure, to which only RF voltages are applied. Ions transmitted through the first quadrupole mass filter (commonly designated as Q1) are accelerated into the collision cell (designated as Q2), where they undergo energetic collisions with molecules or atoms of the collision gas (typically nitrogen or argon) and fragment into product ions by collisionally induced dissociation (CID). The product ions then pass into the second quadrupole mass analyzer (designated as Q3), and the selectively transmitted product ions subsequently strike a detector, which produces a signal representative of the abundance of the transmitted ions. By appropriately controlling the RF and DC voltages applied to Q1 and Q3, different operational modes (e.g., product scans, precursor scans, neutral loss scans, and selective reaction monitoring) may be selected. For example, in the product scan mode, Q1 is operated in a temporally-fixed condition such that it transmits only ions having m/z's within a range corresponding to a precursor ion of interest, while Q3 is scanned (i.e., the m/z range of transmitted ions is temporally ramped) to produce a mass spectrum of the product ions generated by fragmentation of the precursor ion of interest. Another commonly used operational mode for triple quadrupole mass spectrometers is selective-reaction monitoring, whereby complex samples may be screened for the presence of known compounds with high selectivity by operating both Q1 and Q3 in a fixed condition, such that Q1 transmits only ions within an m/z range corresponding to the precursor ion arising from the known compound, and Q3 transmits only ions within a m/z range corresponding to one of its characteristic product ions.
Conventional triple quadrupole mass spectrometers are limited to a single stage of ion selection and fragmentation, commonly referred to as MS/MS analysis. For many applications, it is desirable or necessary to conduct additional stages of ion selection and fragmentation in order to acquire information regarding the m/z's of second or subsequent generation product ions. This information may be useful, for example, for increasing the selectivity of metabolite or drug screening studies, or for providing additional structural elucidation that assists in the sequencing or identification of peptides and other biomolecules. Mass spectrometric analysis of substances utilizing two or more selection/fragmentation stages (referred to herein as MSn analysis) are commonly performed in “tandem-in-time” instruments, such as quadrupole ion trap mass spectrometers or Fourier Transform/Ion Cyclotron Resonance (FTICR) mass spectrometers.
Several approaches for modifying quadrupole mass filter instruments to perform MSn analysis are presented in the prior art. One such approach involves appending one or more collision cells and quadrupole mass filters to a conventional triple quadrupole instrument. For example, Beauregard et al. (Proc. 34th ASMS Conference on Mass Spectrometry and Allied Topics, p. 220) describe a mass spectrometer utilizing five quadrupole rod sets (configured as three quadrupole mass filters and two collision cells). The second quadrupole mass filter is employed to select a first-generation product ion of interest, which is then fragmented in the second collision cell, and a mass spectrum of the resultant second-generation product ions is acquired by scanning the third quadrupole mass filter. However, a mass spectrometer of this description would be complex, bulky and expensive. Furthermore, this approach could not be effectively extended to higher orders of MSn (i.e., n≧4), due to the high transmission losses, which would significantly compromise instrument sensitivity and minimum detection levels.
U.S. Pat. No. 6,504,148 to Hager describes a modified triple quadrupole mass filter architecture in which one of the quadrupole rod sets is selectively operable as a quadrupole mass filter or a linear ion trap. When MSn analysis is desired, the quadrupole rod set is operated as an ion trap so that multiple stages of ion selection and fragmentation may be effected therein. The selected first or subsequent generation product ions are then accelerated into a conventional collision cell where they undergo fragmentation to form second or higher-order product ions. These product ions are then directed through a second quadrupole mass filter for acquisition of a mass spectrum.
Yet another approach is represented by U.S. Pat. No. 6,570,153 to Li et al. and U.S. Pat. No.7,145,133 to Thomson. In this approach, ions derived from a sample are repeatedly passed through one or more quadrupole mass filters by reversing the direction of ion travel within the instrument. For example, an ion sample may be passed through a quadrupole mass filter in a first direction (i.e., from the inlet end to the outlet end) to select a precursor ion of interest. The selected ions are then accelerated into a collision cell located adjacent to the outlet end of the mass filter to produce first generation product ions. The resultant product ions may then be passed through the quadrupole mass filter in the opposite direction (from the outlet end to the inlet end) by adjusting the DC offsets applied to the collision cell, mass filter, and other ion optical components. The mass filter is operated to selectively transmit a first generation product ion of interest, which is then accelerated into a second collision cell located adjacent to the inlet end for production of second-products. This cycle may be repeated to produce and select higher-order generation product ions; when the desired number of ion selection/fragmentation cycles has been completed, the resultant product ions may then be directed to a detector or to another mass analyzer (e.g., a time-of-flight mass analyzer) to obtain a mass spectrum.
The prior art approaches, while technically feasible, require complex electronics that are difficult to implement reliably, and may otherwise result in instrument design problems or have undesired effects on instrument performance. For example, the quadrupole mass filters of the aforementioned Li et al. and Thomson patents, which are operated in a bidirectional fashion, may exhibit different filtering behavior depending on the direction of ion travel, particularly where rod electrodes having a circular-cross section are utilized to construct the mass filter. Also, in this approach the mass filter and adjacent storage/collision cells are blocked for the entire time of analysis, thus increasing time between scans and potentially aggravating space-charge effects in the pre-storage trap. Against this background, there is a need for a mass spectrometer that provides MSn and other advanced capabilities while avoiding the disadvantages associated with prior art approaches.